Abstract:

The present invention relates to a process for the production of
cephalosporin antibiotic intermediate of formula (I). More particularly
relates to the preparation of the compound of formula (I) using a solvent
medium selected from the group consisting of decalin
(decahydronapthalene), hexane, cyclohexene, tetralin, petroleum ether,
wherein X represents HI, HCI, H2SO4 and the like. The compound of formula
(I) is an important intermediate in the preparation of Cefepime.
##STR00001##

Claims:

1. A process for the preparation of compound of formula (I) which
comprises the steps of ##STR00008## i) reacting silylated 7-ACA of
formula (III) ##STR00009## with N-methylpyrrolidine of formula (IV)
##STR00010## or its silylated derivative of formula (V) ##STR00011## in a
solvent medium consisting of hexane, cyclohexene, decalin
(decahydronapthalene), tetralin, petroleum ether or mixtures thereof to
produce compound of formula (VI), ##STR00012## ii) treating the compound
of formula (VI) with aqueous alcoholic solvent or alcoholic solvent or
water andiii) isolating the compound of formula (I).

2. A process as claimed in claim 1, wherein silylated 7-ACA of formula
(III) prepared by reacting 7-ACA of formula (II) with silylating agent in
a solvent consisting of hexanes, cyclohexene, decalin
(decahydronaphthalene), tetralin, petroleum ether, or mixtures there of.

3. A process as claimed in claim 1, wherein silylated by reacting
N-methylpyrrolidine of formula (IV) (NMP) with iodotrimethylsilane in a
solvent consisting of hexanes, cyclohexene, decalin, tetralin or
petroleum ether, or mixtures there of.

Description:

FIELD OF THE INVENTION

[0001]The present invention relates to a process for the production of
cephalosporin antibiotic intermediate of formula (I). More particularly
relates to the preparation of the compound of formula (I).

##STR00002##

wherein X represents HI, HCl, H2SO4 and the like.

[0002]The compound of formula (I) is an important intermediate in the
preparation of Cefepime.

BACKGROUND OF THE INVENTION

[0003]Cefepime is chemically known as
[6R-[6alpha,7beta(Z)]]-1-7-[(2-Amino-4-thiazolyl)(methoxyimino)acetylamin-
o]-2-carboxy-8-oxo-5-thia-1-azabicyclo
[4.2.0]oct-2-en-3-ylmethyl]-1-methylpyrrolidinium hydroxide inner salt or
(6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)-(methoxyimino)acetamido]-3-(1-met-
hylpyrrolidiniomethyl)-3-cephem-4-carboxylate. Cefepime is a
fourth-generation cephalosporin that is active against a wide range of
gram-positive and gram-negative aerobic organisms and is disclosed in
U.S. Pat. No. 4,406,899. According to this patent Cefepime is prepared by
the following process:

##STR00003##

[0004]U.S. Pat. No. 4,868,294 claims a process for the preparation of
stable, crystalline
7-amino-3-[(1-methyl-1-pyrrolidinio)methyl]ceph-3-em-4-carboxylate salts
substantially free of the Δ2 isomer starting from 7-amino
cephalosporanic acid (7-ACA) in 1,1,2-trichlorotrifluoroethane (Freon TF)
or 1,1,1-trichlorotrifluoroethane as the solvent as shown below:

##STR00004##

[0005]U.S. Pat. No. 5,594,531 claims almost a similar process for the
preparation of stable, crystalline
7-amino-3-[(1-methyl-1-pyrrolidinio)methyl]ceph-3-em-4-carboxylate salts
substantially free of the Δ2 isomer by utilizing C5-8
cycloalkanes as solvent.

[0006]During our continued search we have identified solvents, which yield
the compound of formula (I) in good purity, which is substantially free
from Δ2 isomer and useful in the preparation of cefepime.

OBJECTIVE OF THE INVENTION

[0007]The main objective of the present invention is to provide a process
for the preparation of compound of formula (I) in good purity, which is
substantially free from Δ2 isomer.

[0008]Another objective of the present invention is to provide a process
for the preparation of intermediate of formula (I), which is easy to
implement on commercial scale.

SUMMARY OF THE INVENTION

[0009]Accordingly, the present invention provide a process for the
preparation of compound of formula (I)

##STR00005##

which comprises the steps of:i) preparing solution A by reacting
N-methylpyrrolidine of formula (IV) (NMP) with iodotrimethylsilane in a
solvent consisting of hexanes, cyclohexene, decalin, tetralin or
petroleum ether, or mixtures there of,ii) preparing solution B by
reacting 7-ACA of formula (II) with silylating agent in a solvent
consisting of hexanes, cyclohexene, decalin (decahydronaphthalene),
tetralin, petroleum ether, or mixtures there of,iii) condensing solution
A with solution B to produce compound of formula (VI), andiv) treating
the compound of formula (VI) with aqueous alcoholic solvent or alcoholic
solvent or water and isolating the compound of formula (I).The process is
shown in Scheme-2

[0011]In another embodiment of the present invention iodotrimethylsilane
is prepared by reacting hexamethyldisilane (HMD) with iodine at a
temperature in the range of 10° C. to 100° C. in the
presence of solvent selected from hexanes, cyclohexene, decalin, tetralin
or petroleum ether. To this solution NMP was added to yield solution B.

[0012]In another embodiment of the present invention isolation of compound
of formula (I) is carried out by reacting the compound of formula (VI)
obtained in step (iii) with water or lower alkanol or aqueous lower
alkanol such as methanol, isopropyl alcohol, butanol and the like.

[0013]In one more embodiment of the present invention the compound of
formula (I) can be prepared by reacting silylated 7-ACA of formula (II)
with N-methylpyrrolidine of formula (IV) in a solvent consisting of
hexane, cyclohexene, decalin (decahydronapthalene), tetralin, petroleum
ether or mixtures thereof to produce compound of formula (VI), followed
by removing the silyl protecting group of formula (VI). The advantage of
declain over cyclohexane is the solvent recovery is good in the case of
declain, and hence economical from manufacturing point of view.

[0014]In yet another embodiment of the present invention the compound of
formula (I) further converted to cefepime dihydrochloride monohydrate by
the conventional method or by the method disclosed in our co-pending
application No. 673/CHE/2003, 1020/CHENP/03, or 848/MAS/2002.

[0015]In still another embodiment of the present invention the compound of
formula (I) can be prepared by utilizing the following scheme.

##STR00007##

[0016]In yet another embodiment of the present invention, the compound of
formula (VII) is prepared by reacting silylated 7-ACA of formula (III)
with iodotrimethylsilane in the presence of solvent selected from
hexanes, cyclohexene, decalin, tetralin or petroleum ether or mixtures
thereof.

[0017]The present invention is provided by the examples below, which are
provided by way of illustration only and should not be considered to
limit the scope of the invention.

[0020]The silylated 7-ACA solution [Solution B] was added to the Solution
A at to 0° C. The suspension was heated to 34-37° C. and
maintained till completion of reaction. After the completion of the
reaction, reaction mixture was cooled to 3-5° C. Chilled water
(100 mL, -50 to -55° C.) was added at 5-10° C. to
de-silylate followed by/methanol and conc. HCl (30.4 mL). The temperature
was allowed to raise 15° C. and stirred for 15 min. The aqueous
phase was separated and organic phase was extracted with a 50% aqueous
methanol (25.6 mL). To combined aqueous phase, methanol, sodium
metabisulphite, EDTA and carbon, were added, stirred at 10-14° C.
and filtered. The product was crystallized by adding triethylamine and
adjusting the pH to 3.0-3.2 at 15-20° C. The slurry was cooled to
-5 to 0° C. The solid obtained was filtered and washed with
chilled 10% aqueous methanol followed by chilled methanol. Dried under
vacuum at 35-40° C. to yield pure title compound.

[0023]The silylated 7-ACA solution [Solution B] was added to the Solution
A at 0° C. The suspension was heated to 34-37° C. and
maintained till completion of reaction. After the completion of the
reaction, reaction mixture was cooled to 3-5° C. Chilled 50%
aqueous methanol (200 mL, -50 to -55° C.) was added at
5-10° C. followed by conc. HCl (30.4 mL). The temperature was
allowed to raise 15° C. and stirred for 15 min The aqueous phase
was separated and organic phase was extracted with a 50% aqueous methanol
(25.6 mL). To combined aqueous phase, methanol, sodium metabisulphite (1
g) and carbon were added, stirred at 10-14° C. and filtered. The
product was crystallized by adding triethylamine and adjusting the pH to
3.0-3.2 at 15-20° C.

[0024]The slurry was cooled to -5 to 0° C. The solid obtained was
filtered and washed with chilled 10% aqueous methanol followed by chilled
methanol. Dried under vacuum at 35-40° C. to yield pure title
compound.